Diabetes is a chronic, complex metabolic disease that results in the inability of the body to properly maintain and use carbohydrates, fats, and proteins. It results from the interaction of various hereditary and environmental factors and is characterized by high blood glucose levels caused by a deficiency in insulin production or an impairment of its utilization. Most cases of diabetes fall into two clinical types: insulin-dependent diabetes mellitus (IDD or type I diabetes) and non-insulin-dependent diabetes mellitus (NIDD). Each type has a different prognosis, treatment and cause.
In recent years our understanding of the pathophysiology of type I diabetes has increased such that type I diabetes is now generally considered to be a chronic autoimmune disease with a long prodromal phase (Castano et al. (1990) Ann Rev Immunol 8:647-679; Maclaren et al. (1988) Diabetes 37:591-594; Lernmark et al. (1989) Clin Immunol Immunopath 53:358-399). During this prodromal phase and at the onset of overt diabetes, one or more autoantibodies are usually present. Three abnormalities predictive of type I diabetes are cytoplasmic islet cell autoantibodies (ICA) in excess of 20 JDF units (Bonifacio et al. (1990) Lancet 335:147-149), insulin autoantibodies (IAA) detected with fluid phase radioassays in association with islet cell autoantibodies (Ziegler et al. (1989) Diabetes 38:1320-1325), and first phase insulin release less that than the first percentile during an intravenous glucose tolerance test (Vardi et al. (1991) Diabetologia 34:93-102).
Identification of the prediabetic state in diabetes is essential in efforts to prevent the development of the disease. Perhaps the single most important advance of the past two decades in diabetes research has been recognition that autoimmune destruction of beta cells takes months or years to reach completion, whereas currently the clinical diagnosis of diabetes is almost never made until the destructive process is nearly complete and insulin injections are required to prevent death. Intervention before the insulin-producing cells have been irreversibly destroyed can provide a strategy to prevent progression of diabetes and its complications.
Cytoplasmic ICA have been extensively evaluated for the prediction of the development of type I diabetes. They have been found to be a highly predictive marker, particularly if present in high titer (Riley et al. (1990) N Engl J Med 323:1167-1172; Ziegler et al. (1989) Diabetes 38:1320-1325) Nevertheless, in all reported studies of more than five years of prospective observation of ICA positive first degree relatives of type I diabetics, a significant number of relatives have not progressed to diabetes.